The rate at which pharmaceutically active compounds dissolve in gastrointestinal fluids is of crucial importance in the design and use of orally administered medications. The active compound must be dissolved before it can be absorbed by the body. The rate at which the active substance enters into solution is known in the art as the dissolution rate, and the determination of the dissolution rate in vitro is known as dissolution testing.
The concept of using in vitro data to predict or model in vivo behavior, referred to as in vitro-in vivo correlation, or IVIVC, is of great interest to the pharmaceutical arts. Test methods with good IVIVC are much more capable of detecting problems with existing formulations and in the development of new formulations. Systems which correlate closely with the dissolution and absorption data obtained in vivo can be used in developing dosage forms as well as in the production, scale-up, determination of lot-to-lot variability, testing of new dosage strengths, testing of minor formulation changes, testing after changes in the site of manufacture and for determining bio-equivalence.
Various methods and devices for dissolution measurement are well known and described in the art.
The US Food and Drug Administration (US FDA) has issued guidelines on the levels of correlation that are more or less desirable in in vitro testing (Guidance for Industry, Extended Release Oral Dosage Forms: Application of In vitro/In vivo Correlations, September 1997). A Level A correlation is one that predicts the entire in vivo time course from the in vitro data. A Level B correlation is one that uses statistical moment analysis. The mean dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. A Level C correlation establishes a single point relationship between a dissolution parameter and a pharmacokinetic parameter. Level B and Level C correlations do not reflect the complete shape of the plasma concentration-time curve. A Multiple Level C correlation relates in vitro data at several time points to several pharmacokinetic parameters. It is generally considered that if a multiple level C is possible, then Level A correlation should also be possible. Rank order correlations are those where only a qualitative relationship exists between in vitro and in vivo.
A Level A correlation is considered to be the most informative and is recommended by the USFDA wherever possible. Multiple Level C correlations can be as useful as Level A, but a Level A is preferred. Having a high level of correlation, eg Level A, can reduce the amount of in vivo testing necessary for new formulations and can therefore be very valuable to pharmaceutical companies.
The conditions that affect dissolution in the gastro-intestinal system are known to vary with position within the gastro-intestinal system. These variations can affect the rate of dissolution of active substances. There have been attempts to simulate these changes in in vitro testing. The main focus has been on the very large pH change between the stomach and upper GI. This change is large enough to have a very serious effect on the solubility of some active substances. For example, diclofenac sodium is essentially insoluble at the low pH of the stomach, but is soluble at the near neutral conditions of the upper GI. In the current art this change of pH has been addressed in two ways. The first has been to change the fluid used in the dissolution test, for example start with gastric fluid and then change to intestinal fluid. The second has been to change the pH gradually by addition of a higher pH solution. Neither of these methods adequately simulates the pH change in vivo because in both methods all the formulation experiences the pH change at the same time, whereas in vivo the pH change is controlled by gastric emptying which causes a gradual transfer of the disintegrated formulation so that different portions of the formulation experience the pH changes at different times. In U.S. Pat. No. 5,807,115, Hu states that it is difficult to move an already disintegrated solid sample. Hu uses this conclusion to justify the gradual change of pH described above.
A method that has been used to solve the problem associated with the USP fixed volume and flow-through methods has been the continuous flow cell in which either the contents of the cell is stirred, or a part of the effluent is recycled to the cell. This allows equilibrium effects to be evaluated.
The equipment described by Huynh-Ngoc and Sirois (J. Pharm Belg, 1976, 31, 589-598; ibid 1977, 32, 67-75) is a continuous flow apparatus. The equipment was designed to facilitate replacement of gastric fluid with intestinal fluid to simulate the transit of the test material through the gastrointestinal system. The authors establish only a rank order IVIVC. Takenaka, Kawashima and Lin (J. Pharm Sci, 69, 1388-1392, 1980) describe an apparatus similar in form to that of Huynh-Ngoc and Sirois. The authors made no connection between their data and in vivo performance, although it is clear to one skilled in the art that the limitations will be the same as those for the Huynh-Ngoc and Sirois equipment. Pernarowski, Woo, and Searl (J. Pharm Sci, 57, 1419-1421, 1968) also report the use of a continuous flow method. The authors do make comparison of their results with in vivo performance but it is only a rank order correlation.
In all of the flow-through systems described above only one cell is used per test. There are multiple cell systems available commercially, but these have multiple cells in parallel so that each cell is independent of the other and hence they are a plurality of single cell systems. Dissolution testing provides a better understanding of the amount of a pharmaceutically active compound available at a particular absorption site at various times. In addition, establishing a relationship between dosage form and availability of a pharmaceutically active compound at certain absorption sites and systemic blood levels of such active compound aids in the development of specialized delivery techniques.
In U.S. Patent Application Publication Nos. 2007/0092404 and 2007/0160497, improved continuous flow dissolution test apparati, similar to that described in U.S. Pat. No. 6,799,123 are disclosed, along with methods for using them. In particular, U.S. Patent Application Publication No. 2007/0092404 describes using a filter support in the chamber of the second cell, positioned between the filter and the base (interior bottom surface) of the chamber to prevent distortion of the filter as it collects undissolved solids thereon.
On the other hand, U.S. Patent Application Publication No. 2007/0160497 discloses a sample holder device which operates with the sample addition port of the lid of a cell to enable addition and removal of a dosage form to the chamber within the same cell, during continuous operation of the multiple flow-through cell dissolution test system, without having to stop the flow of media or expose the contents of the chamber to the ambient environment.
There is also need for an in vitro test that can be used with different dosage forms of the same active ingredient that gives Level A IVIVC for other dosage forms without the need for different test conditions for each dosage form.